PROJECT SUMMARY In general, men and women experience differing degrees of age-related decreases in physical function, with women having a greater prevalence of functional limitations and disability. A key predictor of this decrease in functional capacity is the reduction in leg muscle maximal power (product of force and velocity), which can be improved with exercise training. However, the development of exercise interventions to optimally improve skeletal muscle function in older adults has been difficult, in part because we now know that men and women respond differently to the same exercise training stimulus. In fact, the fundamental mechanisms by which habitual exercise improves physical function in older adults are still not well understood. The proposed studies, which build upon our recent work, are designed to address these knowledge gaps by examining the molecular and cellular mechanisms underlying the response to two distinct exercise training paradigms, and determining how these responses differ between older men and women. We hypothesize that molecular, cellular and whole muscle contractile performance will be most improved in men by traditional low-velocity, high-load resistance training, and in women by high-velocity, low-load power training. Moreover, sex-specific structural responses in myofilament remodeling, protein expression and post- translational modifications will explain these sex-specific performance adaptations to each modality. To test our hypotheses, data will be gathered from 50 healthy, sedentary older men and women (65-75 years) prior to and following a 16-week unilateral exercise training program in which one leg undergoes resistance training and the other power training. The Specific Aims of this project are to identify the sex-specific effects of low-velocity resistance training versus high-velocity power training on: Aim 1) skeletal muscle function at the molecular, cellular and whole muscle levels, and Aim 2) protein expression and modification as well as size at the molecular and cellular levels. Our within subject, unilateral intervention design provides a powerful model to minimize the effects of between-subject variability, and our translational approach will take advantage of our unique expertise with state-of-the-art measures from the molecular to whole body levels. Our results will challenge conventional wisdom by determining the sex-specific responses in intrinsic skeletal muscle adaptations to different exercise training programs. We will advance scientific knowledge by providing critically- needed information regarding the specific molecular and cellular determinants that support exercise-induced improvements in muscle performance. This knowledge will have a significant positive impact on the clinical care of older adults by providing novel insight about optimal exercise interventions to improve skeletal muscle function in each sex, and by identifying potential new therapeutic targets for pharmaceutical interventions. Thus, this project is highly relevant to the mission and vision of NIA to support biological research to mitigate conditions associated with aging that may limit health and independence in older adults.